This invention relates to a sample handling system. More particularly it relates to a sample handling system wherein the sample is a fluid containing particles.
Large scale sample handling systems which are used in laser scattering particle characterisation apparatus typically contain 1 liter of dispersant in which a large amount of sample, typically 2.5-5 grams, is dispersed resulting in millions of particles being carried. The resulting suspension is then continually re-circulated from a storage reservoir to a measurement cell to allow measurement. As a result of the large number of particles the loss of a small percentage of particles from the measured sample by trapping at crevices, seals and by sedimentation does not significantly bias the results of the measurements.
However, as the volume of dispersant in the system decreases so does the number of particles that can be introduced into the system and the impact upon the particle characterisation measurements of losing even a small percentage of the particles is highly significant, as it is imperative that the portion of the sample presented to the laser beam must be representative of the sample as a whole. This is particularly important in that mechanisms for particle loss are size sensitive thus leading to a skewing of the measured particle size distribution.
A drive to miniaturise sample handling systems has arisen, principally from pharmaceutical drug discovery trials where the drug of interest may cost up to £100 k per gram. Therefore, only a small sample will be used in characterisation experiments and as high a recovery rate of the sample as possible is desirable.
Another reason for miniaturisation is the use of exotic, expensive and possibly noxious dispersants, such as dimethyl sulphoxide (DMSO) or tetrahydrofuran (THF), which must be recovered after use. The significance of the dispersant is apparent when considering the xe2x80x9cwash downxe2x80x9d of the system. The system must be flushed up to 3 times after use in order to prevent cross contamination between measurement sets. Thus, for a 1 liter system up to 4 liters of dispersant must be used for each measurement set. It is therefore desirable to improve upon the basic features of large-scale sample handling systems (a schematic of which is shown in FIG. 1) whilst gaining additional benefits from the miniaturisation of the system.
Current small-scale sample handling systems have a total volume of approximately 150 ml per fill volume and use 0.2 to 0.5 grams of particles per sample. These sample handling systems have a number of further biases associated with them that can skew the measurement results including limitations upon the density of particles that can be measured as it requires a high pump power to keep heavy particles moving in a uniform random suspension. As particle size increases the volume increases as the cube of the particle diameter whereas the viscous drag forces, which maintain the particle in suspension, vary as the square of the diameter. Therefore, the particle size density drag force relationship is very important, for example 100 xcexcm silicon particles will typically settle from suspension in water in a second, thereby severely limiting the available data acquisition period.
A number of solutions to this problem have been applied to small volume systems including where a syringe is used to inject the sample directly into the measurement cell and measurements are made before the particles can settle out. Another solution to the problem of settling out is the use of a rotating stirrer bead (flea) on the base of a narrow sample cuvette (as shown in FIG. 2). This has the problem that only the region of the sample near to the flea is adequately stirred with dead volumes away from the flea receiving only poor agitation. There is also only a very weak agitation in the vertical direction with such motion only arising from the interactions of the fluid with the walls of the cuvette. This arrangement can also result in stratification of the particles within the cuvette with coarse materials being more concentrated in the lower half of the cell, for example. Additionally the flea is optimised to operate in a circular beaker not a cuvette of narrow rectangular cross-section. Therefore an excessively long light path would need to be used if the cuvette were to be optimised for the use of a flea.
One proposed alternative method of maintaining the suspension of particles is the use of a horizontally rotating paddle in a cuvette (as shown in FIG. 3). This system does have disadvantages associated with it including regions where there is poor agitation, typically in the corners of the cell where deposits of coarse particles can form. A further problem is that the particles follow preferred trajectories that are dictated by their particle size. This can result in the formation of strata within the cell, the strata containing different particle size populations by virtue of the preferred trajectories and thus skewing measurement results. Also at higher speeds of rotation of the paddle the system acts as a centrifuge throwing larger particles out to the sides of the cell and depleting those particles from the central volume, where measurements are usually taken, which again skews measurement results.
The use of a manual pre-stir and measurement after particles have settled into Brownian motion and sedimentation is known, however, this is only feasible with very fine particles as the time taken for a measurement is typically longer than the time taken for the particles to settle in such a system.
Many systems use an ultrasonic transducer in order to disperse the particles within the suspension and also a degree of agitation of the particles occurs due to the sonication. There are two usual forms of ultrasonic transducer, the first being a limpet style of transducer which is attached to the outer surface of the tank wherein the suspension is stored, the second type of ultrasonic transducer is an in-line probe which is in effect immersed in the solution.
The use of a limpet style transducer attached to the sample tank in a large volume system typically does not give a high degree of coupling of the sonication energy into the sample. This arrangement is inefficient as only a small amount of displacement is caused for a large energy input.
The in-line probe type of transducer (see for example FIG. 4) yields excellent coupling of the sonication energy into the sample. However, there are regions around the probe and its entry point into the flow path, which will not be well flushed with liquid and could present a potential source of particle trapping and therefore biasing of the system. There is also the problem of large potential power losses at the seal between the internal and external parts of the probe.
Also as the transducer only covers a small area of the tank in a large volume system it is possible that a large proportion of the sample may bypass the ultrasonic transducer and thereby avoid being agitated.
The majority of sample handling systems have a tank in which a large volume of sample, i.e. particulate matter and dispersant, are stored. As it is difficult to achieve uniform agitation of particles with any appreciable density or size variation there is a tendency to size separation within the tank. As a result of this separation it is difficult to find a level at which the outlet to the pump is free of any bias. The sample return from the measurement cell can also significantly bias a tank system, as it is possible that coarse material xe2x80x9cshort circuitxe2x80x9d the tank and pass straight back into the pump inlet thus the material passing through the measurement cell will be unrepresentative of the true bulk nature of the sample and appear overly coarse.
The sample drain also presents a number of problems as current drains utilise the fact that the pump cavity floor is typically the lowest part of the flow path and thus the pump cavity floor is made so that it can drop away and the sample can drain from this point. Provided that the actuator closing the drain is sufficiently powerful then the floor can be clamped without there being any additional gaps to trap particles or dead volumes. This does however rely on the fact that the pump cavity is below the level of the tank and as there is a desire to minimise volume, storage tanks will be reduced in size or ideally eliminated in these small volume systems, this may not be possible.
It is an object of the present invention to ameliorate at least one of the aforementioned disadvantages.
It is a preferred object of the invention to provide a sample handling system in which the overall volume of the system is reduced.
It is a preferred object of the invention to provide a sample handling system in which the number of sites at which deposition of particles in the sample can occur is minimised.
It is a preferred object of the invention to provide a sample handling system in which particle reclamation is maximised when the sample is drained from the system.
It is a preferred object of the invention to provide a sample handling system in which the portion of the sample presented in a measurement zone at any time is substantially representative of the sample as a whole.
It is a preferred object of the invention to provide a sample handling system in which the efficiency of the ultrasonic transducer is improved in order to reduce heating of the system and to ensure that substantially all of the particles pass over an ultrasonically active region thereby enhancing the dispersion and de-aggglomeration of the particles.
Other objects, features and benefits of the invention will be understood from the description herein.
Thus, according to the broadest aspect of the invention there is provided a sample handling system, preferably a small volume system, in which skewing or distortion of measurements is reduced or eliminated by improvements to one or more features of the system such as flow paths, mixing and suspension of the sample.
As used herein the term xe2x80x98small volumexe2x80x99 is intended to define a system in which the total volume is 100 ml or less, preferably 80 ml or less and more preferably 50 ml or less and most preferably 30 ml or less.
According to a first aspect of the present invention there is provided a particle suspension handling system comprising:
a dispersion unit;
a transport element,
a cell;
said dispersion unit including at least one wall;
a transducer being mounted upon said at least one wall, externally of said dispersion unit and being arranged, in use, to transfer energy into the suspension; and
said transport element being located within said dispersion unit and being arranged, in use, to recirculate the suspension about a flow path including said dispersion unit and said cell.
The system may have a total volume of 80 ml or less. The transducer may be an ultrasonic transducer, The transport element may be arranged to remove cavitation bubbles from the at least one wall, in use. The transducer may extend over substantially all of the at least one wall. The transport element may be an impeller. Substantially all of the suspension may flow over the at least one wall, in use.
Particle characterisation apparatus having a detector arranged to detect signals dependant upon the characterisations of particles in a test sample, and a volume particle suspension handling systems according to the first aspect of the present invention.
Desirably the dispersion unit is in the form of a chamber. The chamber may form a pump chamber and may have an impeller mounted therein. The impeller may have blades, which may be equi-angularly spaced The base of the chamber may be a flat surface forming a diaphragm. Preferably the combined volume of the inlet means and dispersion unit is less than 50 ml, more preferably less than 30 ml, very preferably less than 25 ml or optimally less than 20 ml.
Additionally, the dispersion unit may include an ultrasound unit. The ultrasound unit may be attached to the diaphragm, or alternatively it may form the base of the pump chamber. The ultrasound unit may extend over substantially all of the base area of the pump chamber. In use, the ultrasound unit may cause cavitation across the base of the pump chamber. Preferably the impeller clears the cavitation bubbles from the base of the pump chamber thereby increasing the degree of coupling of the ultrasonic energy with the sample. Ideally substantially all of the sample flows past the ultrasound unit during its cycle around the sample handling system. The ultrasound unit need only be used periodically. The ultrasound unit may cause the de-agglomeration of aggregates of small particles.
According to a second aspect of the present invention there is provided a particle suspension handling system comprising:
a dispersion unit;
a cell;
an outlet region;
the outlet region including first and second valve members, said first and second members being configured, in a first arrangement, wherein said members are spaced apart such that the space between said members is a discharge opening via which a fluid or the suspension exits the system in use;
the members being configured, in a second arrangement, wherein the members abut and a flow path of substantially constant cross-section is provided about the outlet region.
The system may have a total volume of 80 ml or less. A gallery in the second member may be arranged to place an input opening and an output opening of the first member in said flow path when the members are in their second configuration. A biasing element may be arranged to retain the first and second members in abutment, in use. The biasing element may be a spring. An actuation element may be arranged to relatively displace the first and second members between said first and second configurations. The actuation element may include a servomotor. A biasing element may be arranged to retain the first and second members in abutment, in use, and an actuation element may be arranged to relatively displace the first and second members between said first and second configurations, the bias of the biasing element may be sufficient to retain the members in their second configuration should the actuation element fail. The biasing element may be a spring and the actuation element may include a servomotor. A face of the second member, opposite a face of the first member, may be spaced apart from the first member, in the first configuration, such that a fluid exiting an outlet of the first member may flow over substantially all of the face of the second member, in use. There may be provided a collection chamber adjacent said discharge opening which may be arranged to capture the fluid or suspension which exits the system in the first configuration, in use.
Particle characterisation apparatus having a detector arranged to detect signals dependant upon the characterisations of particles in a test sample and having a small volume particle suspension handling system according to the second aspect of the present invention.
The outlet region has open and closed configurations. In the closed configuration the outlet region may constitute an unbroken flow path within the sample handling system thereby reducing the number of possible sites for deposition of a particulate carried in the sample. The outlet region may have input and output and discharge openings. The input and output openings may form part of an unbroken flow path when the outlet region are in the closed configuration. Preferably the discharge opening receives the majority of the dispersant when the outlet region are in the open configuration. The outlet region may be formed from first and second members and a drain region. Preferably the first and second members are in mutual abutment in the closed configuration. Ideally the first and second members are spaced apart in the open configuration. The space between the first and second members may define the discharge opening. Preferably the drain region is adjacent to the discharge opening. The first member may be a manifold having both input and output openings therein and the second member may be a block with a gallery therein which conjoins the input and output openings in the closed configuration and may be semi-elliptical in cross-section. Alternatively the first and second members may be an O ring and a tube respectively. Another alternative is that both first and second members may be tubes. A biasing element may retain the first and second members in abutment. The biasing element may be a coiled spring or other suitable type of spring, for example a leaf spring. The first and second members may be moved from abutment by an actuation element. The actuation mechanism may be electromechanical or alternatively may be manual. Preferably the bias of the biasing element is such that should the actuation element fail the first and second members will be positively retained in mutual abutment. The drain region may substantially surround the first and second members. Preferably the face of the second member is displaced from the first member when they are in the open configuration, such that when the system is flushed with clean dispersant the region of the face around the input and output opening is washed by the clean dispersant.
According to a third aspect of the present invention there is provided a particle suspension handling system comprising:
a dispersion unit;
a transport element;
a cell;
said dispersion unit including at least one wall;
an ultrasonic transducer being mounted upon said at least one wall, externally of said dispersion unit and being arranged, in use, to transfer ultrasonic energy into the suspension;
said transport element being located within said dispersion unit and being arranged, in use, to recirculate the suspension about a flow path including said dispersion unit and said cell; and
the total volume of the system being 80 ml or less.
According to a fourth aspect of the present invention there is provided a particle suspension handling system comprising:
a dispersion unit;
a cell;
an outlet region;
the outlet region including first and second valve members, said first and second members being configured, in a first arrangement, wherein said members are spaced apart such that the space between said members is a discharge opening via which a fluid or the suspension exits the system, in use;
the members being configured, in a second arrangement, wherein the members abut and a flow path of substantially constant cross-section is provided about the outlet region;
a face of the second member, opposite a face of the first member, is spaced apart from the first member, in the first configuration, such that a fluid exiting an outlet of the first member flows over substantially all of the face of the second member, in use; and
a gallery in the second member is arranged to place an input opening and an output opening of the first member in said flow path when the members are in their second configuration; and the system has a total volume of 80 ml or less.
According to another aspect of the present invention there is provided a method of characterising a property of a fluid or a dispersion comprising the steps of:
I. Using a small volume sample handling system according to any of the other aspects of the present invention to maintain the fluid or dispersion in motion;
II. Passing radiation through a window in a measurement cell of the sample handling system;
III. Collecting radiation affected by the fluid or dispersion;
IV. Analysing the radiation affected by the fluid or dispersion in order to characterise a property of the fluid or dispersion.
Preferably the dispersion comprises a dispersant and a particulate. The particulate may be a pharmaceutical compound. Desirably the radiation is monochromatic. The radiation may be provided by a laser and will therefore be both monochromatic and coherent. The radiation affected by the fluid or dispersion may have suffered any or all of absorption, scattering or attenuation. Ideally radiation affected by a dispersion is analysed to characterise a particle size distribution within the dispersion.
According to yet another aspect of the invention there is provided a small volume sample handling system comprising an integrally formed inlet means and dispersion means, a measurement cell and outlet means, the inlet means, dispersion means, measurement cell and outlet means being interconnected so as to provide a circulatory flow path; the dispersion means also acting as a pump means.
According to a further aspect of the present invention there is provided a small volume sample handling system comprising an inlet means, a dispersion means, a measurement cell and outlet means all being interconnected so as to provide a circulatory flow path, the measurement cell having a flowpath therethrough and a window therein, the window forming a first part of a wall of the flowpath being flush with a second part of the wall of the flowpath.
According to another aspect of the present invention there is provided a small volume sample handling system comprising an inlet means, a dispersion means, a measurement cell, and outlet means all being interconnected so as to provide a circulatory flowpath, the outlet means having a bore of constant cross-sectional area therethrough.
According to a still further aspect of the present invention there is provided a sample handling system comprising an inlet means, a dispersion, a cell and outlet means.